Composition comprising a crystallographically stable, amorphous cephalosporin and processes for the preparation thereof

ABSTRACT

Processes are provided for the preparation of orally administrable, yellow and powdery compositions essentially consisting of particles composed of a homogeneous mixture of an amorphous Cefditoren pivoxil substance with a water soluble high-molecular additive. These compositions can be produced by dissolving crystalline Cefditoren pivoxil substance and the water-soluble high-molecular additive in an aqueous solution of an acid, then neutralizing the resultant solution, to co-precipitate the product, and drying the thus precipitated product, followed by recovering the product in the form of the above-mentioned particles.

This application is a division of Ser. No. 09/582,937 filed Jan. 7, 2000U.S. Pat. No. 6,342,493 which is a national stage of PCT/JP99/00020filed Jan. 7, 1999.

TECHNICAL FIELD

This invention relates to an orally administrable and powderycomposition consisting essentially of a number of particles eachcomprising a crystallographically stable and amorphous cephalosporin.More specifically, this invention relates to a novel, orallyadministrable and powdery composition consisting essentially ofparticles which each have a uniform internal texture within eachparticle and each are formed from a homogeneous mixture of an amorphousand water-soluble substance of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, that is,Cefditoren pivoxil (a generic name), with a water-soluble,high-molecular additive, for example, a water-solubilized derivative ofcellulose. This invention further relates to processes for thepreparation of the novel, orally administrable and powdery compositionas above-mentioned.

BACKGROUND ART

The cephem compound known under the generic name “Cefditoren” is thecompound which is represented by the following formula (A)

and which compound was at first named as7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylicacid (syn-isomer, cis-isomer) (refer to Japanese Patent Publication Hei3-64503 specification, U.S. Pat. No.4,839,350 and European PatentNo.0175610 specification).

Cefditoren pivaloyloxymethyl ester is a pro-drug known under the genericname “Cefditoren pivoxil” and is the compound represented by thefollowing formula (B)

Cefditoren pivoxil is also known in the name of“(−)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2,2-dimethylpropionyloxymethyl ester” and is described on page 317of the literature “Merck Index”, the 12th Edition to be a paleyellow-colored powdery substance melting at 127˜129° C. Another chemicalname of the compound “Cefditoren pivoxil” is7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester.

Cefditoren pivoxil, when orally administered, can be well absorbed bythe digestive tracts, within which Cefditoren pivoxil is hydrolyzed intoCefditoren. It is known that Cefditoren is an antibiotic substancepossessing an extremely broad antibacterial spectrum but a low toxicityand Cefditoren is very excellently useful for the therapeutic treatmentand prevention of diseases which are caused by gram-positive andgram-negative bacteria. At present, Cefditoren pivoxil is widelyutilized as an orally administrable pro-drug for the therapy.

We, the present inventors, had made investigations with the intention ofobtaining a highly pure product of Cefditoren pivoxil, and as a result,we already succeeded in obtaining Cefditoren pivoxil in the form of anorthorhombic crystalline substance (at a purity of: 97˜98%) of a meltingpoint of 206˜215.7° C. (with decomposition), by adopting a certainparticular process (refer to International Open-Laying Publication No.WO98/12200 of PCT application No. PCT/JP97/03340, issued on Mar. 26,1998). This orthorhombic crystalline substance of Cefditoren pivoxilshows such advantages that it has a high purity, a high thermalstability and a high storage-stability under high-humidity conditions,but still it shows such disadvantage that it itself is not so suitablefor the purpose of oral administrations due to its poor solubility inwater.

DISCLOSURE OF INVENTION

In general, for such medicinal compounds which are sparingly soluble inwater, it is well known that the solubility or the dissolution speed ofthe sparingly water-soluble compounds in water can exert a greatinfluence on the absorption in vivo of said compounds. Thus, manyreports were presented on how to improve the water-solubility of suchmedicinal compounds which are sparingly soluble in water. One of thereported proposals is a method in which a medicinal compound sparinglysoluble in water is converted into an amorphous substance, thus toimprove the solubility of the compound in water. It is known that anamorphous substance generally has a higher solubility in water, ascompared with that of the corresponding crystalline substance. It istherefore expectable that if the orthorhombic crystalline substance ofCefditoren pivoxil sparingly soluble in water is converted into anamorphous substance which is of a higher solubility in water, there maybe afforded such a water-soluble and highly pure product of Cefditorenpivoxil which is capable of exhibiting its therapeutic efficacy to afull extent.

We have therefore further prosecuted diligently our investigations inorder to solve the problem of converting the crystalline Cefditorenpivoxil into an amorphous substance having a higher water-solubility. Asa result, we have now found that there can successfully be prepared anorally administrable, yellow-colored powdery composition consistingessentially of such particles which each have a uniform internal textureor tissue within each particle and which each are formed from ahomogeneous mixture of the amorphous Cefditoren pivoxil substance havinga high water-solubility and a high thermal stability, with awater-soluble high-molecular additive, when use is made of such aprocess which comprises dissolving a crystalline Cefditoren pivoxil inan acidic aqueous solution containing a water-soluble high-molecularadditive, for example, a water-solubilized derivative of cellulose andan acid dissolved therein, thereby to form an acidic aqueous solutioncontaining Cefditoren pivoxil, the water-soluble high-molecular additiveand the acid dissolved therein, then slowly adding to the resultantacidic aqueous solution an aqueous solution of an inorganic base toneutralize said acidic aqueous solution to a neutral or a substantiallyneutral pH value, with co-precipitating Cefditoren pivoxil and saidwater-soluble high-molecular additive simultaneously from said aqueoussolution during the neutralization operation, then washing the depositedprecipitate with an aqueous solution of the water-soluble high-molecularadditive, drying the washed precipitate, and recovering the resultingparticulate product so dried. This invention has been established on thebasis of these findings mentioned above.

Thus, according to a first aspect of this invention, there is providedan orally administrable, yellow-colored powdery composition consistingessentially of solid particles which each are formed of a homogeneousmixture of a crystallo-graphically stable, amorphous and water-solublesubstance of Cefditoren pivoxil with a water-soluble high-molecularadditive, and which particles have a uniform, internal texture withineach particle, characterized in that said yellow-colored powderycomposition consists essentially of the solid particles each formed ofthe homogeneous mixture of (i) the crystallographically stable,amorphous and water-soluble substance of Cefditoren pivoxil, namely7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester, with (ii) the water-soluble high-molecularadditive which is either such a pharmaceutically acceptable,water-solubilized derivative of cellulose as chosen fromhydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate,hydroxypropyl cellulose, methyl cellulose and a pharmaceuticallyacceptable alkali metal salt or alkaline earth metal salt ofcarboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone oran alginic acid ester of polypropylene glycol, that the water-solublehigh-molecular additive (ii) contained in the above-mentioned solidparticles is present in said particles in a proportion of 0.5%˜5% basedon the weight of the Cefditoren pivoxil substance, that said particlesfuse at a temperature of 120° C. or higher, but do not show any definitemelting point, that the amorphous substance of Cefditoren pivoxil (i)contained in said particles does not show any peak of the angle ofdiffraction in a X-ray powder diffractometry chart of said particles butexhibits in its infrared absorption spectrum (as measured by pelletedpotassium bromide method) a substantially broader peak of absorption ata wave number of 1750 cm⁻¹, as compared with the sharp peak ofabsorption exhibited by the orthorhombic crystalline substance ofCefditoren pivoxil at a wave number of 1750 cm⁻¹ in the infraredabsorption spectrum, and that the amorphous substance of Cefditorenpivoxil (i) contained in said particles can be dissolved in an acidifiedwater containing hydrochloric acid (pH 1.2) at a solubility of at least4 mg/ml of Cefditoren pivoxil at 37° C. and has a crystallographicalstability such that said amorphous Cefditoren pivoxil substance does notinvolve crystallization when stored at 40° C. for 4 months in a sealedcontainer under dry conditions.

One preferred example of the powdery composition according to the firstaspect of this invention is such a composition consisting essentially ofparticles each formed of a homogeneous mixture of a crystallographicallystable, amorphous and water-soluble substance of Cefditoren pivoxil withthe water-soluble high-molecular additive which is hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose orpolyvinylpyrrolidone, and which additive as blended is present in aproportion of 1%˜3% based on the weight of the Cefditoren pivoxil.

Further, in respect of the respective solid particles which each areformed of the homogeneous mixture of the amorphous Cefditoren pivoxilwith the water-soluble high-molecular additive and which are present inthe powdery composition according to the first aspect of this invention,we have now observed, under a polarizing microscope of 400magnifications or under an electron microscope, the surface texture ortissue of said solid particles, and we have found that the surface ofeach particle has a simple and uniform texture or tissue. We cannot findany presence of independent and separate grains of either Cefditorenpivoxil or the high-molecular additive in the surface of each particle.

In the powdery composition according to the first aspect of thisinvention, the water-soluble high-molecular additive which is to bemixed with the amorphous Cefditoren pivoxil, and which is thewater-solubilized cellulose derivatives, or pluran, carraqeenan,polyvinylpyrrolidone or an arginic acid ester of polypropylene glycol,may be of a grade thereof which usually is used and incorporated in theformulations of medicines as a binder or a suspending agent. Among thewater-soluble high-molecular additives to be usable in the compositionof the first aspect of this invention, the water-solubilized derivativesof cellulose are particularly preferred. As the water-solubilizedderivatives of cellulose, there may be used hydroxypropylmethylcellulose (abbreviated as HPMC), hydroxypropylmethyl cellulose phthalate(abbreviated as HPMCP), hydroxypropyl cellulose (abbreviated as HPC),methyl cellulose (abbreviated as MC), carboxymethyl cellulose calciumsalt or carboxymethyl cellulose sodium salt. The use ofhydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) ormethyl cellulose (MC) is particularly preferred.

In the homogeneous mixture which constitutes the solid particles presentin the powdery composition of the first aspect of this invention, andwhich is composed of the amorphous Cefditoren pivoxil and thewater-soluble high-molecular additive, the proportion of thewater-soluble high-molecular additive to be incorporated therein may bein a range of 0.5%˜5%, preferably in a range of 1%˜3% based on theweight of Cefditoren pivoxil.

Further, we have tried to measure the melting point of the solidparticles present in the composition of the first aspect of thisinvention, by placing the particles in a melting point-measuringapparatus. As a result, we have found that these solid particles fuse at120˜150° C. with decomposition, but do not show any one definite meltingpoint.

We have further carried out the measurement of powder X-ray diffractionof the solid particles present in the composition of the first aspect ofthis invention, by placing the particles in a X-ray powder diffractionapparatus (Rigaku Denki K. K. : Geigerflex 2027). Upon analysis of thepattern of the resulting X-ray diffraction chart of said X-ray powderdiffraction, it is shown that no peak is appearing in the angle ofdiffraction, indicating that the Cefditoren pivoxil substance existingin said solid particles is amorphous in nature.

We have further carried out a measurement of infrared absorptionspectrum of the solid particles present in the composition of the firstaspect of this invention, by mixing the solid particles with an amountof potassium bromide, compressing the resultant mixture to pelletize thesame, and then placing the resulting pellet into an infrared absorptionspectrometer. In the spectrum chart thus obtained, the infraredabsorption spectrum of the Cefditoren pivoxil substance present in saidpowder exhibits at a wave number of 1750 cm⁻¹ an absorption peak whichis substantially broader than such a sharp absorption peak that theorthorhombic crystalline substance of Cefditoren pivoxil exhibits at awave number of 1750 cm⁻¹ in its infrared absorption spectrum.

We have also made a measurement of powder X-ray diffraction of thepreviously stored solid particles present in the composition of thefirst aspect of this invention, by placing and storing said solidparticles in a sealed container under a dry air atmosphere at 40° C. for4 months, followed by measuring the powder X-ray diffraction of thestored particles in the powder X-ray diffraction apparatus used asabove. Analysis of the pattern of the resulting powder X-ray diffractionchart did not indicate any peak in the angle of diffraction in thechart. Thus, it is demonstrated that the Cefditoren pivoxil present inthe particles stored as above has remained in the amorphous state andthat it is crystallographically stable and can maintain the amorphousstate even after the storage thereof for a long period of time.

We presume that in the composition of this invention, the water-solublehigh-molecular additive co-existent in admixture with the Cefditorenpivoxil in the solid particles can possess a function capable ofinhibiting the molecules of Cefditoren pivoxil from undergoing theircrystallization.

The solid particles present in the composition of this invention have anaverage particle diameter within the range of 0.5 μ˜100 μ.

The solid particles present in the composition of this invention weretested for the measurement of their water-solubility as shown in TestExample given hereinafter. It was thus found that the amorphousCefditoren pivoxil contained in said particles was soluble in anacidified water of pH 1.2 containing about 0.1 N hydrochloric acid(corresponding to the artificial gastric juice specified in JapanesePharmacopedia) and had a solubility of at least 4 mg/ml in the acidifiedwater at 37° C.

Furthermore, we have proceeded our further investigation. Thus, when wecarry out, for the purpose of producing the particles of the powderycomposition of the first aspect invention, the process which comprisesthe steps of completely dissolving a crystalline Cefditoren pivoxil inan acidic aqueous solution containing and having dissolved therein awater-soluble high-molecular additive and an acid, thereby to prepare anacidic aqueous solution containing Cefditoren pivoxil, the water-solublehigh-molecular additive and the acid all dissolved therein, then slowlyadding to the resulting acidic aqueous solution so prepared an aqueoussolution of an inorganic base, thereby to neutralize the acidic aqueoussolution to a neutral pH value or a substantially neutral pH value,allowing, during the neutralization operation, Cefditoren pivoxil andthe first-mentioned water-soluble high-molecular additive toco-precipitate simultaneously from said aqueous acidic solution,separating and then washing the deposited precipitate with an aqueoussolution of the first-mentioned a water-soluble high-molecular additiveand subsequently drying the washed precipitate, we have now found thatthe aforesaid process can be carried out in such one modified mannerthat the first mentioned water-soluble high-molecular additive, whichwas contained in said acidic aqueous solution of the water-solublehigh-molecular additive and the acid to be employed for the dissolutionof Cefditoren pivoxil, and which is to be contained in the washingaqueous solution of the high-molecular additive for washing thedeposited precipitate, is replaced by such a second, water-solublehigh-molecular additive which is made of a compound different from saidfirst-mentioned high-molecular additive, when it is intended to preparea washing aqueous solution of the water-soluble high-molecular additivewhich is to be employed in the step of washing said deposited recipitatetherewith, and thereby at least a portion of the second, water-solublehigh-molecular additive present in so prepared the washing aqueoussolution of the second additive as employed for the aforesaid washingstep is allowed to transfer into the surface of the precipitateparticles during said washing step. It has further been found that, whensaid washing step is conducted with said aqueous solution of thesecond-mentioned additive, followed by conducting the steps ofrecovering and drying the precipitate particles of which the surfacehave contained therein the second, water-soluble high-molecular additiveas transferred from the washing aqueous solution employed in saidwashing step, there can be afforded such dried precipitate particleswherein the surface layer of each of said solid particles as collectedis formed from a homogeneous mixture of the amorphous Cefditoren pivoxilwith the first, water-soluble high-molecular additive and the second,water-soluble high-molecular additive, but wherein the central portionor core portion of each of the solid particles lying under the surfacelayer of the solid particles is formed from a homogeneous mixture of theamorphous Cefditoren pivoxil with the first, water-solublehigh-molecular additive.

According to a second aspect of this invention, therefore, there isprovided an orally administrable, yellow-colored powdery compositionconsisting essentially of particles which each substantially comprisemixtures of a crystallographically stable, amorphous and water-solublesubstance of Cefditoren pivoxil with water-soluble high-molecularadditive or additives, and which particles have a uniform, internaltexture within each particle, characterized in that the yellow-coloredpowdery composition consists essentially of the particles eachsubstantially comprising a mixture of (i) the crystallographicallystable, amorphous and water-soluble substance of Cefditoren pivoxil,namely7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester, with (ii) a first, water-solublehigh-molecular additive which is either such a pharmaceuticallyacceptable, water-solubilized derivative of cellulose as chosen fromhydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate,hydroxypropyl cellulose, methyl cellulose and a pharmaceuticallyacceptable alkali metal salt or alkaline earth metal salt ofcarboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone oran alginic acid ester of polypropylene glycol, that the central portionor core portion of the respective particles which is lying under thesurface layer of said respective particles is formed only from ahomogeneous mixture of (i) the amorphous substance of Cefditoren pivoxilwith (ii) the above-mentioned first, water-soluble high-molecularadditive, but the surface layer of said particles is formed from ahomogeneous mixture of (i) the amorphous substance of Cefditoren pivoxilwith (ii) the first, water-soluble high-molecular additive and also with(iii) such a second, water-soluble high-molecular additive which isadditionally incorporated and which second additive is made of asubstance different from the above-mentioned first, water-solublehigh-molecular additive present just in the central portion or coreportion of said particles lying under said surface layer of theparticle, and which second, water-soluble high-molecular additive isselected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose,methyl cellulose and polyvinylpyrrolidone, that both the first,water-soluble high-molecular additive (ii) and the second, water-solublehigh-molecular additive (iii) are present in a total proportion of themof 0.5%˜5% based on the weight of the Cefditoren pivoxil substancecontained in said particles, that said particles fuse at a temperatureof 120° C. or higher, but do not show any definite melting point, thatthe amorphous substance of Cefditoren pivoxil (i) contained in saidparticles does not show any peak of the angle of diffraction in a powderX-ray diffractometry chart of said particles but exhibits in itsinfrared absorption spectrum (as measured by pelleted potassium bromidemethod) a substantially broader peak of absorption at a wave number of1750 cm⁻¹, as compared with the sharp peak of absorption exhibited bythe ortho-rhombic crystalline substance of Cefditoren pivoxil at a wavenumber of 1750 cm⁻¹ in the infrared absorption spectrum, and that theamorphous substance of Cefditoren pivoxil (i) contained in saidparticles can be dissolved in an acidified water containing hydrochloricacid (pH 1.2) at a solubility of at least 4 mg/ml of Cefditoren pivoxilat 37° C. and has a crystallographical stability such that saidamorphous Cefditoren pivoxil substance does not involve crystallizationwhen stored at 40° C. for 4 months in a sealed container under dryconditions.

A first preferred example of the powdery composition according to thesecond aspect of this invention is such a composition, wherein thecentral portion or core portion of the particles constituting thecomposition, which is lying under the surface layer of the particles, isformed from a homogeneous mixture of the amorphous substance ofCefditoren pivoxil with hydroxypropylmethyl cellulose, but the surfacelayer of said particles is formed from a homogeneous mixture of theamorphous substance of Cefditoren pivoxil with hydroxypropylmethylcellulose and also with hydroxypropyl cellulose or methyl cellulose.

A second preferred example of the powdery composition according to thesecond aspect of this invention is such a composition, wherein thecentral portion or core portion of the particles constituting thecomposition, which is lying under the surface layer of the particles, isformed from a homogeneous mixture of the amorphous substance ofCefditoren pivoxil with hydroxypropylmethyl cellulose, but the surfacelayer of said particles is formed from a homogeneous mixture of theamorphous substance of Cefditoren pivoxil with hydroxypropyl celluloseand also with hydroxypropylmethyl cellulose or methyl cellulose.

A third preferred example of the powdery composition according to thesecond aspect of this invention is such a composition, wherein thecentral portion or core portion of the particles constituting thecomposition, which is lying under the surface layer of the particles, isformed from a homogeneous mixture of the amorphous substance ofCefditoren pivoxil with methyl cellulose, but the surface layer of saidparticles is formed from a homogeneous mixture of the amorphoussubstance of Cefditoren pivoxil with methyl cellulose and also withhydroxypropylmethyl cellulose or hydroxypropyl cellulose.

A fourth preferred example of the powdery composition according to thesecond aspect of this invention is such a composition, wherein thecentral portion or core portion of the particles constituting thecomposition, which is lying under the surface layer of the particles, isformed from a homogeneous mixture of the amorphous substance ofCefditoren pivoxil with polyvinylpyrrolidone, but the surface layer ofsaid particles is formed from a homogeneous mixture of the amorphoussubstance of Cefditoren pivoxil with polyvinylpyrrolidone and also withhydroxypropylmethyl cellulose or hydroxypropyl cellulose or methylcellulose.

The solid particles present in the composition of the second aspect ofthis invention have physical and physicochemical propertiessubstantially the same as those of the solid particles present in thecomposition according to the first aspect of this invention.

Besides, the solid particles present in the composition according to thesecond aspect of this invention have been found to be such those that,when the surface of the particles are observed under a polarizingmicroscope or under an electron microscope, said surface has a simpleand uniform, internal texture in each particle and does notsubstantially contain any independently separate grains of Cefditorenpivoxil, nor any independently separate grains of the water-solublehigh-molecular additives in the surface texture or tissue of saidparticles.

Both of the powdery composition according to the first aspect of thisinvention and the powdery composition according to the second aspect ofthis invention are orally administrable, and they may be formulated inthe form of tablets by blending said composition with excipient(s), forexample, starch or talc, and/or binder(s), for example, gelatine orhydroxypropyl cellulose, and a suitable additive agent, and thencompressing the resulting blend into tablets. Both of the powderycompositions according to the first and second aspects of this inventionmay also be formulated in the form of powdery preparations by blendingsuch composition with a pharmaceutically acceptable powdery carrier, forexample, starch or cellulose powder.

For a process for the preparation of the powdery composition accordingto the first aspect of this invention, there is provided, according to athird aspect of this invention, a process for the preparation of ayellow-colored powdery composition consisting essentially of particleswhich each are formed of a homogeneous mixture of a crystallographicallystable, amorphous and water-soluble substance of Cefditoren pivoxil witha water-soluble high-molecular additive, and which particles have auniform, internal texture within each particle, characterized in thatthe process comprises a step of dissolving an orthorhombic crystallinesubstance of Cefditoren pivoxil, namely7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester, in an acidic aqueous solution which iscontaining a water-soluble high-molecular additive made of either such awater-solubilized derivative of cellulose as chosen fromhydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate,hydroxypropyl cellulose methyl cellulose and a pharmaceuticallyacceptable alkali metal salt or alkaline earth metal salt ofcarboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone oran alginic acid ester of polypropylene glycol as dissolved at aconcentration of 0.05% to 1% (weight/weight basis), and which acidicaqueous solution is containing also hydrochloric acid, phosphoric acid,sulfuric acid, acetic acid, propionic acid or butyric acid at aconcentration of 0.1N˜12N of the acid, so that the amount of Cefditorenpivoxil dissolved in said acidic aqueous solution is in the range of 10times to 130 times based on the whole weight of said water-solublehigh-molecular additive contained in said acidic aqueous solution, andso that there is prepared an acidic aqueous solution containingCefditoren pivoxil, the water-soluble high-molecular additive and theacid dissolved therein; a step of subsequently neutralizing the acidicaqueous solution so prepared by adding slowly thereto an aqueoussolution or solutions of sodium or potassium hydroxide, sodium orpotassium hydrogen carbonate, or sodium or potassium carbonate, singlyor in combination, or an aqueous solution of ammonium hydroxide, withmaintaining said acidic aqueous solution at a temperature of 10° C. orbelow under stirring, and with the amount of the basic sodium orpotassium compound or ammonium hydroxide to be added to said acidicaqueous solution being so adjusted that the resulting reaction solutionafter the neutralization shows a pH value of 6.5˜7.1; and a step ofcontinuing during the neutralization reaction the stirring of theaqueous solution containing Cefditoren pivoxil at a temperature of 10°C. or below, to bring about co-precipitation of Cefditoren pivoxil andthe water-soluble high-molecular additive simultaneously from theaqueous solution; a step of collecting by filtration or centrifugation,the so deposited precipitate from the resulting neutralization reactionmixture; a step of washing the collected precipitate with an aqueoussolution of a water-soluble high-molecular additive made of the samesubstance as that of the first-mentioned water-soluble high-molecularadditive and containing said additive dissolved in said solution at aconcentration of 0.5%˜10% (weight/weight basis), while at least aportion of said water-soluble high-molecular additive used here in thewashing aqueous solution is allowed during the washing operation totransfer from the washing aqueous solution of the water-solublehigh-molecular additive into the surfaces of the particles of saidprecipitate; and a step of then drying the washed precipitate, to affordthe yellow-colored powdery composition consisting essentially of theparticles each formed of the homogeneous mixture of thecrystallographically stable, amorphous and water-soluble substance ofCefditoren pivoxil with the above-mentioned water-soluble high-molecularadditive present in a proportion of 0.5%˜5% based on the weight of theCefditoren pivoxil substance.

In practicing the process of the third aspect of this invention, theacid present in the aqueous solution of the water-soluble high-molecularadditive and the acid to be used for the dissolution of the crystallineCefditoren pivoxil substance may preferably be hydrochloric acid,phosphoric acid, acetic acid or sulfuric acid. Particularly,hydrochloric acid is preferred. The concentration of the acid in saidaqueous solution may be within a range of 0.1N˜12N, with a range of0.5N˜2.0N being particularly preferred.

The step of dissolving the crystalline Cefditoren pivoxil substance inthe acidic aqueous solution containing said water-soluble high-molecularadditive and acid may preferably be carried out at a temperature of 10°C. or lower. The dissolution of the crystalline Cefditoren pivoxilsubstance may preferably be effected with taking a period of time of10˜60 minutes therefor. By adopting these operation conditions, it isnecessary to make the Cefditoren pivoxil substance dissolved completelyin the aqueous solution of the water-soluble high-molecular additive andthe acid.

Next, there is effected the step of neutralizing the resulting aqueoussolution of the Cefditoren pivoxil, water-soluble high-molecularadditive and acid, with an inorganic base. The aqueous solution of aninorganic base used for this neutralization step may preferably be anaqueous ammonium hydroxide solution, namely aqueous ammonia, or aqueoussodium hydroxide solution, aqueous potassium hydroxide solution, aqueoussodium hydrogen carbonate solution or aqueous potassium hydrogencarbonate solution. Aqueous ammonia is particularly preferred. Theconcentration of the inorganic base in the aqueous solution of theinorganic base may be in a range of 0.1N˜14N, but the base concentrationin a range of 0.5N˜2.0N is particularly preferred. An aqueous solutionof one inorganic base may be used in combination with an aqueoussolution of another inorganic base. The addition of the aqueous solutionof the inorganic base is preferably carried out slowly, whilemaintaining the neutralization reaction mixture at a temperature of 0°C.˜10° C. The addition may preferably be effected dropwise. The time tobe taken for the neutralization reaction may be 5 minutes˜24 hours andpreferably 5 minutes˜10 hours. During the neutralization reaction, it ispreferred that the amount of the inorganic base added is so controlledthat the resulting reaction mixture shows a pH value of 6.5˜7.0 at thecompletion of the neutralization. With the progress of theneutralization reaction, Cefditoren pivoxil and the water-solublehigh-molecular additive are allowed to be co-precipitated simultaneouslyfrom the aqueous solution, resulting in the deposition of solidprecipitate. This precipitate is composed of a mixture of Cefditorenpivoxil with the water-soluble high-molecular additive.

After the completion of the neutralization reaction, the precipitate isthen collected from the resulting neutralization reaction mixture. Thecollection of the precipitate may be effected by filtration, forexample, filtration under a reduced pressure, or by centrifugation, in aconventional manner.

Next, the precipitate so collected is subjected to the step of washingit at a temperature of 10° C. or below with an aqueous solutioncontaining such a water-soluble high-molecular additive which is of thesame compound as the high-molecular additive just co-precipitated andthus included in said precipitate and which high-molecular additive ispresent at a concentration of 0.5%˜10% (weight %) in said aqueoussolution. By this washing operation, the salts having attached to theprecipitate can be removed, and at least a portion of the water-solublehigh-molecular additive present in the washing aqueous solution isallowed to transfer into the surface of the precipitate particles fromthe washing aqueous solution of the water-soluble high-molecularadditive during the washing operation. If a plain water were used forthe step of washing the precipitate, a portion of the water-solublehigh-molecular additive which has been included and contained in theprecipitate could be washed away therefrom. In such a possible case, theparticles of the powder which could be obtained after a drying of theprecipitate so washed with the plain water would be undesirable as thetarget product wanted, because the content of the water-solublehigh-molecular additive in the particles should be unsuitably lower thanthe desirable one. Such undesirable product is inappropriate in that theCefditoren pivoxil component contained therein can show some tendency tocrystallize out.

The precipitate which has received the washing step as above is thendried in a conventional way. The drying step is preferably carried outat a temperature of 30° C. or lower under a reduced pressure. Thus, asthe dried final product, there can be afforded a powdery compositionconsisting essentially of solid particles which each are formed of ahomogeneous mixture of a crystallographically stable, amorphous andwater-soluble substance of Cefditoren pivoxil and the water-solublehigh-molecular additive as mixed in a proportion of 0.5%˜5% (weight %)of said additive, based on the weight of the Cefditoren pivoxilsubstance.

Preferably, the process of the third aspect of this invention may beeffected by such a process comprising a step of dissolving theorthorhombic crystalline substance of Cefditoren pivoxil in an acidicaqueous solution which is containing such a water-soluble high-molecularadditive as chosen from hydroxypropylmethyl cellulose, hydroxypropylcellulose, methyl cellulose and polyvinylpyrrolidone as dissolved at aconcentration of 0.05% to 1% (weight/weight basis) and which acidicaqueous solution is containing also hydrochloric acid or phosphoric acidat a concentration of 0.5N˜2.0N of the acid, so that the amount ofCefditoren pivoxil dissolved in said acidic aqueous solution is in arange of 10 times to 100 times based on the whole weight of saidwater-soluble high-molecular additive contained in said acidic aqueoussolution, and so that there is prepared an acidic aqueous solutioncontaining Cefditoren pivoxil, the water-soluble high-molecular additiveand the acid dissolved therein; a step of subsequently neutralizing theso prepared acidic aqueous solution containing Cefditoren pivoxil, byadding slowly thereto a 1N˜2N aqueous sodium hydroxide solution or/and a1N˜2N aqueous sodium hydrogen carbonate solution, or by adding slowlythereto a 1N˜2N aqueous ammonium hydroxide solution, with maintainingsaid acidic aqueous solution at a temperature of 5° C. or below understirring, until said acidic aqueous solution is neutralized to a pHvalue of 6.5˜7.0; a step of continuing during the neutralizationreaction the stirring of the resulting neutralization reaction mixtureat a temperature of 5° C. or below, to bring about co-precipitation ofCefditoren pivoxil and the water-soluble high-molecular additivesimultaneously from said aqueous solution; a step of collecting the sodeposited precipitate from the resulting neutralization reactionmixture; a step of washing the collected precipitate with an aqueoussolution of a water-soluble high-molecular additive made of thesubstance same as that of the first-mentioned water-solublehigh-molecular additive and containing said additive dissolved in saidsolution at a concentration of 0.5%˜10% (weight/weight basis); and astep of then drying the washed precipitate, to afford the yellow-coloredpowdery composition consisting essentially of the particles each formedof a homogeneous mixture of the amorphous substance of Cefditorenpivoxil with the above-mentioned water-soluble high-molecular additivepresent in a proportion of 1%˜3% based on the weight of the Cefditorenpivoxil substance.

For a process for the preparation of the powdery composition of thesecond aspect of this invention, there is provided, according to afourth aspect of this invention, a process for the preparation of ayellow-colored powdery composition consisting essentially of particleswhich each comprise mixtures of a crystallographically stable, amorphousand water-soluble substance of Cefditoren pivoxil with water-solublehigh-molecular additive or additives, and which particles have auniform, internal texture within each particle, characterized in thatthe process comprises a step of dissolving an orthorhombic substance ofCefditoren pivoxil in an acidic aqueous solution which is containing afirst water-soluble high-molecular additive made of either such awater-solubilized derivative of cellulose as chosen fromhydroxy-propylmethyl cellulose, hydroxypropylmethyl cellulose phthalate,hydroxypropyl cellulose, methyl cellulose and a pharmaceuticallyacceptable alkali metal salt or alkaline earth metal salt ofcarboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone oran alginic acid ester of polypropylene glycol as dissolved at aconcentration of 0.05%˜1% (weight/weight basis) and which acidic aqueoussolution is containing also hydrochloric acid, phosphoric acid, sulfuricacid, acetic acid, propionic acid or butyric acid at a concentration of0.1N˜12N of the acid, so that the amount of Cefditoren pivoxil dissolvedin said acidic aqueous solution is in a range of 10 times to 130 timesbased on the whole weight of said first water-soluble high-molecularadditive contained in said acidic aqueous solution, and so that there isprepared an acidic aqueous solution containing Cefditoren pivoxil, thefirst, water-soluble high-molecular additive and the acid dissolvedtherein; a step of subsequently neutralizing the so prepared acidicaqueous solution, by adding slowly thereto an aqueous solution orsolutions of sodium or potassium hydroxide, sodium or potassium hydrogencarbonate, or sodium or potassium carbonate, singly or in combination,or by adding slowly thereto an aqueous solution of ammonium hydroxide,with maintaining said acidic aqueous solution at a temperature of 10° C.or below under stirring, and with the amount of the basic sodium orpotassium compound or ammonium hydroxide to be added to said acidicaqueous solution being so adjusted that the reaction solution after theneutralization shows a pH value of 6.5˜7.1; a step of continuing duringthe neutralization reaction the stirring of the aqueous solutioncontaining Cefditoren pivoxil at a temperature of 10° C. or below, tobring about co-precipitation of Cefditoren pivoxil and the first,water-soluble high-molecular additive simultaneously from the aqueoussolution; a step of collecting by filtration or centrifugation the sodeposited precipitate from the resulting neutralization reactionmixture; a step of washing the collected precipitate with such anaqueous solution which is containing a second, water-solublehigh-molecular additive made of a substance different from theabove-mentioned first, water-soluble high-molecular additive containedin said acidic aqueous solution containing Cefditoren pivoxil, and whichaqueous solution is containing said second high molecular additivedissolved therein at a concentration of 0.5%˜10% (weight/weight basis),while at least a portion of said second water-soluble high-molecularadditive used here in the washing aqueous solution is allowed during thewashing operation to transfer from the washing aqueous solution of thesecond water-soluble high-molecular additive into the surfaces of theparticles of the precipitate; and a step of then drying the washedprecipitate, to afford the yellow-colored powdery composition consistingessentially of such particles which each contains Cefditoren pivoxil,and of which the central portion or core portion of each particle isformed only from a homogeneous mixture of the crystallographicallystable, amorphous and water-soluble substance of Cefditoren pivoxil withthe first water-soluble high-molecular additive present in a proportionof 0.5%˜5% based on the weight of said Cefditoren pivoxil substance, andof which the surface layer of each particle is formed from a homogeneousmixture of the crystallographically stable, amorphous and water-solublesubstance of Cefditoren pivoxil with said first water-solublehigh-molecular additive and also with said second water-solublehigh-molecular additive.

The process of the fourth aspect of this invention may be carried out inthe same manner as the process of the third aspect of this invention.

The process of the fourth aspect of this invention is preferablyeffected by such a process comprising a step of dissolving theorthorhombic crystalline substance of Cefditoren pivoxil in an acidicaqueous solution which is containing such a water-soluble high-molecularadditive as chosen from hydroxypropylmethyl cellulose, hydroxypropylcellulose, methyl cellulose and polyvinylpyrrolidone as dissolved at aconcentration of 0.05%˜1% (weight/weight basis) and which acidic aqueoussolution is containing also hydrochloric acid or phosphoric acid at aconcentration of 0.5N˜2.0N of the acid, so that the amount of Cefditorenpivoxil dissolved in the acidic aqueous solution is in a range of 10times to 100 times based on the whole weight of said first water-solublehigh-molecular additive contained in said acidic aqueous solution, andso that there is prepared an acidic aqueous solution containingCefditoren pivoxil, the water-soluble high-molecular additive and theacid dissolved therein; a step of subsequently neutralizing the soprepared acidic aqueous solution containing Cefditoren pivoxil, byadding slowly thereto an aqueous 1N˜2N sodium hydroxide solution or/andan aqueous 1N˜2N sodium hydrogen carbonate solution or by adding slowlythereto an aqueous 1N˜2N ammonium hydroxide solution, with maintainingthe acidic aqueous solution at a temperature of 5° C. or below understirring, until the acidic aqueous solution is neutralized to a pH valueof 6.5˜7.0; a step of continuing the stirring of the neutralizationreaction mixture at a temperature of 5° C. or below during theneutralization reaction, to bring about the co-precipitation ofCefditoren pivoxil and said first water-soluble high-molecular additivesimultaneously from the aqueous solution; a step of collecting thedeposited precipitate from the resulting neutralization reactionmixture; a step of washing the collected precipitate with such anaqueous solution which is containing, as the second water-solublehigh-molecular additive made of a substance different from theabove-mentioned first water-soluble high-molecular additive, such awater-soluble high-molecular additive as chosen from hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose andpolyvinylpyrrolidone, and which aqueous solution is containing saidsecond high-molecular additive dissolved therein at a concentration of0.5%˜10% (weight/weight basis), while at least a portion of the secondwater-soluble high-molecular additive used here in the washing aqueoussolution is allowed during the washing operation to transfer from saidaqueous solution of the second water-soluble high-molecular additiveinto the surfaces of the particles of the precipitate; and a step ofthen drying the washed precipitate, to afford the yellow-colored powderycomposition consisting essentially of such particles of which thecentral portion or core portion of each particle is formed only from ahomogeneous mixture of the amorphous substance of Cefditoren pivoxilwith said first water-soluble high-molecular additive, and of which thesurface layer of each particle is formed from a homogeneous mixture ofthe amorphous substance of Cefditoren pivoxil with said firstwater-soluble high-molecular additive and also with said secondwater-soluble high-molecular additive.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a pattern of a powder X-ray diffraction chart obtained bymeasuring in a powder X-ray diffractometer the powdery composition whichconsists essentially of particles as formed from a homogeneous mixtureof the amorphous substance of Cefditoren pivoxil withhydroxypropylmethyl cellulose, and which was produced in Example 6 ofthis invention given hereinafter.

FIG. 2a shows an infrared absorption spectrum (as measured by thepelleted KBr method) of the Cefditoren pivoxil component contained inthe particles which are essentially formed from the homogeneous mixtureof the amorphous substance of Cefditoren pivoxil withhydroxypropylmethyl cellulose, and which were produced in Example 6 ofthis invention given hereinafter.

FIG. 2b shows an infrared absorption spectrum (as measured by thepelleted KBr method) of the crystalline substance of Cefditoren pivoxil(which is the orthorhombic crystalline substance as obtained in Example1 of the PCT International Open-Laying Publication No. WO98/12200). Thearrows given in these charts of the infrared absorption spectra indicatethe absorption peaks at the wave number of 1750 cm⁻¹.

BEST MODE FOR CARRYING OUT THE INVENTION

Now, this invention is concretely illustrated with reference to typicalExamples thereof, but is not limited to these Examples. The crystallinesubstance of Cefditoren pivoxil used in Example 1˜14 given hereinafteris the orthorhombic crystalline substance of Cefditoren pivoxil (mp.215° C., a purity of about 97%) obtained in Example 1 of the PCTInternational open Laying Publication No. WO98/12200.

The following Examples 1˜3 illustrate the preparation of theyellow-colored powdery composition according to the first aspect of thisinvention, and Examples 4˜14 illustrate the preparation of theyellow-colored powdery composition according to the second aspect ofthis invention.

EXAMPLE 1

The crystalline substance (20 g) of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester, namely Cefditoren pivoxil, was dissolvedin an acidic aqueous solution (140 ml) containing hydroxypropylcellulose (200 mg) as dissolved therein and hydrochloric acid at aconcentration of 1N of HCl, with taking a time of 11 minutes for thedissolution of Cefditoren pivoxil therein. During this dissolutionoperation, the aqueous solution was maintained at a temperature of 5° C.or lower. Thus, there was prepared an acidic aqueous solution (pH 0.6)in which Cefditoren pivoxil had been completely dissolved. This acidicaqueous solution containing Cefditoren pivoxil was then neutralized (toa pH of 7.0) by a dropwise slow addition of a 1N aqueous ammonia (about138 ml) thereto over a time period of 60 minutes at a temperature of 5°C. or lower. There occurred the deposition of precipitate. The resultingneutralization reaction mixture containing the precipitate as depositedwas then stirred overnight at a temperature of 5° C. or lower.

The deposited precipitate was collected by filtration of said reactionmixture, and was then washed well with an aqueous solution of 0.5% (byweight) of hydroxypropyl cellulose (60 ml). The precipitate so washedwas dried under a reduced pressure. Thus, there was afforded 19.6 g of ayellow-colored powder (the composition of this invention) consistingessentially of numerous fine particles which each were formed of ahomogeneous mixture of the amorphous substance of Cefditoren pivoxilwith hydroxypropyl cellulose. When observation was made, under anelectron microscope (magnification:×10000), of the surface of the fineparticles present in the resulting yellow-colored powder, it was shownthat the surface of these fine particles had a simple and uniform phaseor texture.

The content of hydroxypropyl cellulose contained in the fine particlespresent in said resulting yellow-colored powder was calculated, from ananalysis by means of a gas chromatography, to be 1% (by weight) on thebasis of the Cefditoren pivoxil component. Further, by analyzing saidfine particles in the above-mentioned powder X-ray diffractionapparatus, it was found that no peak was appearing in the angle ofdiffraction in the pattern of the resulting X-ray diffraction chart, andtherefore that the Cefditoren pivoxil component present in these fineparticles was in the form of the amorphous substance.

EXAMPLE 2

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved inan acidic aqueous solution (35 ml) containing hydroxypropylmethylcellulose (50 mg) as dissolved therein and 1N HCl, at a temperature of5° C. or lower and with taking a time of 10 minutes for the dissolutionof Cefditoren pivoxil. Thus, there was prepared an acidic aqueoussolution (pH 1.32) in which Cefditoren pivoxil had been completelydissolved. The resulting aqueous solution containing Cefditoren pivoxilwas then neutralized (up to a pH of 6.9) by a dropwise slow addition ofa 1N aqueous ammonia (about 33 ml) thereto over the time period of 30minutes at a temperature of 5° C. or lower. There occurred thedeposition of precipitate. The resulting neutralization reaction mixturewas then stirred overnight at a temperature of 5° C. or lower. Thedeposited precipitate was collected by filtration, and was then washedwell with an aqueous solution (15 ml) of 0.5% (by weight) ofhydroxypropylmethyl cellulose. The precipitate so washed was dried undera reduced pressure. Thus, there was afforded 4.9 g of a yellow-coloredpowder (the composition of this invention) consisting essentially ofnumerous fine particles which each were formed of a homogeneous mixtureof the amorphous substance of Cefditoren pivoxil withhydroxy-propylmethyl cellulose.

The content of hydroxypropylmethyl cellulose contained in the fineparticles present in the resulting yellow-colored powder was calculatedto be 1% (by weight) on the basis of the Cefditoren pivoxil component.Further, by analyzing said fine particles in the above-mentioned powderX-ray diffraction apparatus, it was found that the Cefditoren pivoxilcomponent present in these fine particles was in the form of theamorphous substance.

EXAMPLE 3

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved inan acidic aqueous solution (35 ml) containing polyvinylpyrrolidone (50mg) as dissolved therein and HCl at a concentration of 1N, at atemperature of 5° C. or lower and with taking a time of 10 minutes forthe dissolution of Cefditoren pivoxil. Thus, there was prepared anacidic aqueous solution (pH 0.4) in which Cefditoren pivoxil wascompletely dissolved. This aqueous solution was then neutralized by adropwise slow addition of a 1N aqueous ammonia (about 34 ml) theretoover 30 minutes at a temperature of 5° C. or lower. During theneutralization reaction, precipitate deposited. The resultingneutralization reaction mixture (pH: 6.8) containing the precipitate asformed was stirred at a temperature of 5° C. or lower overnight. Thedeposited precipitate was collected by filtration, and was then washedwell with an aqueous solution (15 ml) of 0.5% (by weight) ofpolyvinylpyrrolidone. The precipitate so washed was dried under areduced pressure. Thus, there was obtained 4.9 g of a yellow-coloredpowder consisting essentially of numerous fine particles which each wereformed of a homogeneous mixture of the amorphous substance of Cefditorenpivoxil with polyvinylpyrrolidone.

The content of polyvinylpyrrolidone contained in the fine particlespresent in the resulting yellow-colored powder was calculated to be 1%(by weight) on the basis of the Cefditoren pivoxil component. Byanalyzing the said fine particles in the above-mentioned powder X-raydiffraction analyzer, it was found that the Cefditoren pivoxil componentexisting in these fine particles was in the form of the amorphoussubstance.

EXAMPLE 4

The crystalline substance of Cefditoren pivoxil (10 g) was dissolved inan acidic aqueous solution (100 ml) containing about 1 g ofhydroxypropylmethyl cellulose as dissolved therein (at a concentrationof 1%) and HCl at a concentration of 1N, at a temperature of 10° C. orlower. Thus, there was prepared an acidic aqueous solution in whichCefditoren pivoxil was completely dissolved. This acidic aqueoussolution obtained was then neutralized by a dropwise slow addition of a1N aqueous sodium hydroxide solution (100 ml) thereto, while thetemperature was maintained at 5° C. or lower. During the neutralizationreaction, precipitate slowly deposited from the aqueous solution. Theresulting neutralization reaction mixture containing the precipitate wasstirred overnight at a temperature of 5° C. or lower.

Then, the neutralization reaction mixture was filtered, and theprecipitate thus collected was placed in a filtration apparatus whichwas operated under a reduced pressure. To the filtration apparatus, anaqueous solution of 1% of hydroxypropyl cellulose was added, followed bywashing further the precipitate under pushing pressure. The precipitateso washed was dried under a reduced pressure, and there was thusobtained 9.6 g of a yellow-colored powder consisting essentially ofnumerous fine particles which each were formed from a mixture comprisingCefditoren pivoxil and hydroxypropylmethyl cellulose.

The fine particles present in the resulting yellow-colored powder wereexamined by a powder X-ray diffraction analyzer (Geigerflex 2027, madeby Rigaku Denki K.K.), to obtain a chart of the powder X-ray diffractionof said fine particles. The result of an analysis of the pattern of theresulting X-ray diffraction chart indicated that no peak was seen in theangle of diffraction in the chart, and that the Cefditoren pivoxilcomponent present in the fine particles was in the form of the amorphoussubstance.

The total content of hydroxypropylmethyl cellulose plus hydroxypropylcellulose contained in the fine particles present in the resultingyellow-colored powder was calculated to be 2% (by weight) on the basisof the Cefditoren pivoxil component.

Further, the aqueous solution of hydroxypropyl cellulose which had beenused for the washing operation of the precipitate as collected from theneutralization reaction mixture mentioned in the above was then whollyrecovered after the washing operation. A measurement was then made ofthe total residual amount of the hydroxypropyl cellulose remaining inthe aqueous solution of hydroxypropyl cellulose which had been used inthe washing operation and then recovered as above. The total residualamount so measured of the hydroxypropyl cellulose present in the sorecovered aqueous solution after the washing step was observed to besignificantly less than the initial, total amount of hydroxylpropylcellulose which was initially contained in the aqueous solution ofhydroxypropyl cellulose as just charged in the washing step. Based onthis observed fact, it was deduced that, during the washing operation ofthe precipitate, an amount of the hydroxypropyl cellulose componentpresent as the solute in the washing aqueous solution had transferredinto the precipitate, at least into the surface of the precipitate, fromthe washing aqueous solution of hydroxypropyl cellulose just employed insaid washing step.

Furthermore, when an examination was conducted, under an electronmicroscope (magnification×10000), in respect of several ones of the fineparticles as picked up from the resulting yellow-colored powder asabove, it was shown that the surface of these fine particles had asimple and uniform texture or tissue, and further that in the surface ofthe fine particles, there was substantially not observed any presence ofindependently separate grains of Cefditoren pivoxil or any presence ofindependently separate grains of hydroxy-propylmethyl cellulose or ofhydroxypropyl cellulose.

EXAMPLE 5

The crystalline substance of Cefditoren pivoxil (50 g) was dissolved inan acidic aqueous solution (350 ml) containing hydroxypropylmethylcellulose (500 mg) as dissolved therein and HCl at a concentration of1N, at a temperature of 5° C., and with taking the time over a period of45 minutes for the dissolution of Cefditoren pivoxil. The resultingaqueous solution was filtered through a millipore (1 μm) membrane filterto remove the insoluble solid matters from the solution. Thus, there wasprepared an acidic aqueous solution containing Cefditoren pivoxil andhydroxylpropylmethyl cellulose completely dissolved therein, as well ashydrochloric acid.

The resulting acidic aqueous solution here obtained was then neutralizedto a pH of 3.3 by a dropwise slow addition of a 1N aqueous sodiumhydroxide solution (315 ml), and then to a pH of 7.0 by a slow additionof a 1N aqueous sodium hydrogen carbonate solution (43.5 ml), while thetemperature of the resulting reaction solution was maintained at 5° C.or below. The total period of time taken for the dropwise addition ofthe aqueous solutions of the inorganic bases was 1.5 hours to thecompletion.

During the neutralization reaction, precipitate slowly deposited. Theresulting neutralization reaction solution containing the precipitate asformed was then stirred overnight at a temperature of 5° C. or lower,and then the reaction solution was again adjusted to its pH of 7.0 by adropwise addition of an aqueous 1N sodium hydrogen carbonate solution.

The neutralization reaction mixture here obtained as above was filteredto recover the precipitate therefrom. The resulting precipitate waswashed well with an aqueous solution of 0.5% (by weight) ofhydroxypropyl cellulose (150 ml). The precipitate so washed was thendried under a reduced pressure. There was thus obtained 48.5 g of ayellow-colored powder (the composition of this invention) consistingessentially of numerous fine particles which each were substantiallyformed from a homogeneous mixture comprising the amorphous Cefditorenpivoxil substance and hydroxypropylmethyl cellulose.

The total content of hydroxypropylmethyl cellulose plus hydroxypropylcellulose contained in the fine particles present in the resultingyellow-colored powder was calculated to be 1.1% (by weight) on the basisof the Cefditoren pivoxil component.

The fine particles present in the resulting yellow-colored powder wereplaced in a powder X-ray diffraction analyzer for an examinationthereof. The result of analysis of the pattern of the X-ray diffractionchart so obtained indicated that no peak was seen in the angle ofdiffraction in the chart, and therefore that the Cefditoren pivoxilcomponent contained in the fine particles was present in the form of theamorphous substance. Further, when an examination was made under anelectron microscope in respect of several ones of the fine particles soobtained, it was shown that the surface of the particles had a simpleuniform texture, and that there was substantially not observed thepresence of any independently separate grains in the surface of the fineparticles.

It is deemed that the fine particles present in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and hydroxypropylmethyl cellulose, while the surface layer ofsaid fine particles is formed of a homogeneous mixture comprising theamorphous substance of Cefditoren pivoxil, hydroxypropylmethyl celluloseand hydroxypropyl cellulose.

COMPARATIVE EXAMPLE 1

The procedure of Example 5 was repeated in the substantially same manneras in Example 5, except that the use of both the hydroxypropylmethylcellulose and hydroxypropyl cellulose was completely omitted. In otherwords, the crystalline substance of Cefditoren pivoxil (5 g) wasdissolved in water (50 ml) containing 1N HCl, with taking a period of 23minutes for the dissolution of Cefditoren pivoxil, while the temperatureof the solution was maintained at 5° C. or lower. After the completionof the dissolution of Cefditoren pivoxil in the acidic water, an aqueous1N sodium hydroxide solution (40 ml) was slowly added dropwise to theresulting acidic aqueous solution of Cefditoren pivoxil to neutralizethe latter solution to a pH of 2.1. Then, an aqueous 1N sodium hydrogencarbonate solution (10 ml) was added dropwise to the aqueous solution ofCefditoren pivoxil to neutralize the solution further. During theneutralization step, the reaction solution was maintained at atemperature of 5° C. or lower. Total time taken for the completion ofthe addition of these aqueous solutions of the inorganic bases was 27minutes.

The resulting neutralization reaction mixture containing the precipitateas formed (pH 6.2) was stirred for 1.5 hours at a temperature of 5° C.or lower, and then was neutralized further to a pH of 7.0 by a dropwiseaddition of an aqueous 1N sodium hydrogen carbonate solution.

During the latter neutralization reaction step, precipitate ofCefditoren pivoxil deposited from the aqueous solution. Theneutralization reaction mixture obtained here was stirred at atemperature of 5° C. or lower overnight.

The here obtained neutralization reaction mixture containing theprecipitate was filtered to recover the deposited precipitate. Theprecipitate so collected was washed well with water (25 ml) as cooled to5° C. The precipitate so washed was dried to afford a fine powder (4.4g) which was formed of a crystalline substance of Cefditoren pivoxil.The fine particles present in said fine powder was examined by thepowder X-ray diffraction analyzer, to indicate that a peak was appearingin the angle of diffraction in the pattern of the resulting X-raydiffraction chart. It was thus deduced that the Cefditoren pivoxilcomponent contained in the fine powder obtained here was present in theform of a crystalline substance.

EXAMPLE 6

The crystalline substance of Cefditoren pivoxil (50 g) was dissolvedover 45 minutes in an acidic aqueous solution (350 ml) containinghydroxypropylmethyl cellulose (500 mg) as dissolved therein and HCl at aconcentration of 1N at a temperature of 5° C. or lower. The resultingaqueous solution containing Cefditoren pivoxil was filtered through amillipore (1 μm) membrane filter to remove the insoluble solid matterstherefrom. Thus, there was prepared an acidic aqueous solution in whichCefditoren pivoxil, hydroxypropylmethyl cellulose and hydrochloric acidwere completely dissolved.

The acidic aqueous solution obtained here was neutralized to a pH of 7.0by a dropwise slow addition of a IN aqueous ammonia, namely an aqueoussolution of 1N ammonium hydroxide (331 ml), while the acidic aqueoussolution was maintained at a temperature of 5° C. or lower. The totaltime taken for the completion of the dropwise addition of the aqueousammonia was 1.5 hours. During this neutralization reaction, precipitateslowly deposited. The resulting neutralization reaction mixturecontaining the precipitate as formed was then stirred overnight at atemperature of 5° C. or lower. Then, the pH of the reaction mixture wasagain adjusted to a pH of 7.0 by a dropwise addition of a 1N aqueousammonia.

The neutralization reaction mixture here obtained as above was filteredto recover the precipitate therefrom. The resulting precipitate waswashed well with an aqueous solution of 0.5% (by weight) ofhydroxypropyl cellulose (150 ml). The precipitate so washed was thendried under a reduced pressure. There was thus obtained 48.8 g of ayellow-colored powder (the composition of this invention) consistingessentially of numerous fine particles which each were formedsubstantially from a homogeneous mixture comprising the amorphoussubstance of Cefditoren pivoxil and hydroxypropylmethyl cellulose.

The fine particles present in the resulting yellow-colored powder wasanalyzed by a high performance liquid chromatography, to detect that thefine particles had a content of 96% (by weight) of the Cefditorenpivoxil component based on the weight of the fine particles. Further,the total content of hydroxypropylmethyl cellulose plus hydroxypropylcellulose contained in the fine particles was calculated to be 1.3% (byweight) based on the weight of the Cefditoren pivoxil component.

The fine particles present in the resulting yellow-colored powder wereplaced in and examined by the powder X-ray diffraction analyzer(Geigerflex 2027, made by Rigaku Denki K.K.), to give a chart of thepowder X-ray diffraction of said fine particles. The result of analysisof the pattern of the X-ray diffraction chart revealed that no peak wasseen in the angle of diffraction in the chart, and therefore that theCefditoren pivoxil component contained in the fine particles was presentin the form of the amorphous substance. Further, the examination wasmade under an electron microscope in respect of several ones of the fineparticles, it was shown that the surface of the fine particles had asimple and uniform texture and further that any independently separategrains are substantially absent in the surface of the fine particles.

It is deemed that the fine particles present in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and hydroxypropylmethyl cellulose, while the surface layer ofthe fine particles is formed of a homogeneous mixture comprising theamorphous substance of Cefditoren pivoxil and hydroxypropylmethylcellulose and hydroxypropyl cellulose.

A diffraction chart of the powder X-ray diffraction which was given bymeasuring the fine particles of the yellow-colored powder as produced inthis Example in the powder X-ray diffraction analyzer (Geigerflex 2027,made by Rigaku Denki K. K.), is shown in FIG. 1 of the attacheddrawings.

An infrared absorption spectrum (measured by the pelleted KBr method) ofthe amorphous substance of Cefditoren pivoxil present in the fineparticles just mentioned above was also measured by placing said fineparticles in an infrared spectrometer.

The chart of the infrared absorption spectrum thus obtained is shown inFIG. 2a of the attached drawings. An infrared absorption spectrum wassimilarly measured for the crystalline substance of Cefditoren pivoxilused in this Example as the starting material, and the measured chartthereof is also shown in FIG. 2b of the attached drawings.

COMPARATIVE EXAMPLE 2

The procedure of Example 6 was repeated in substantially the same manneras in Example 6, except that the use of both of hydroxypropylmethylcellulose and hydroxypropyl cellulose was omitted.

Namely, Cefditoren pivoxil in the form of a crystalline substance(20 g)was dissolved over 3 hours in a volume of water (190 ml) containing HClat a concentration of 1N, at a temperature of 5° C. or lower. After thecompletion of the dissolution of Cefditoren pivoxil in the acidifiedwater, the resulting aqueous solution was filtered through a millipore(1.0 μm) membrane filter. The resulting acidic aqueous solutioncontaining Cefditoren pivoxil was then neutralized to a pH of 6.03 by adropwise slow addition of a 1N aqueous ammonia (192 ml), while theacidic solution was maintained at a temperature of 5° C. or lower. Theresulting neutralization reaction mixture containing the precipitate asformed (pH 6.03) was stirred overnight at a temperature of 5° C. orlower, and then 1N aqueous ammonia was again added dropwise to adjustthe pH of the reaction mixture to pH 5.8. During this step of theneutralization reaction, precipitate of Cefditoren pivoxil depositedfrom the aqueous solution. The neutralization reaction mixture obtainedhere was stirred at a temperature of 5° C. or lower overnight.

The resultant neutralization reaction mixture containing the precipitatewas filtered to recover the deposited precipitate. The collectedprecipitate was washed well with cold water at 5° C. (60 ml). Theprecipitate so washed was dried to afford a fine powder (19.4 g) whichwas formed of a crystalline substance of Cefditoren pivoxil. Theresulting fine powder obtained here was examined by the powder X-raydiffraction analyzer, to indicate that a peak was appearing in the angleof diffraction in the pattern of the X-ray diffraction chart soobtained. It is thus confirmed that the Cefditoren pivoxil componentcontained in the resulting fine particles was present in the crystallinesubstance form.

EXAMPLE 7

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved over16 minutes in an acidic aqueous solution (35 ml) containinghydroxypropylmethyl cellulose (50 mg) as dissolved therein and HCl at aconcentration of 1N, at a temperature of 5° C. or lower. Thus, there wasprepared an acidic aqueous solution (pH 0.8) in which Cefditorenpivoxil, hydroxypropylmethyl cellulose and hydrochloric acid werecompletely dissolved.

The resulting acidic aqueous solution was neutralized to a pH of 6.7 bya dropwise slow addition of a 1N aqueous ammonia (about 34 ml), whilethe acidic aqueous solution was maintained at a temperature of 5° C. orlower. The time taken for the completion of the dropwise addition of theaqueous ammonia was 33 minutes. During the neutralization reaction,precipitate slowly deposited. The resulting neutralization reactionmixture containing the precipitate as formed was stirred overnight at atemperature of 5° C. or lower.

The neutralization reaction mixture obtained here was filtered tocollect the precipitate. The resulting precipitate was washed well withan aqueous solution of a 0.5% (by weight) of hydroxypropyl cellulose (75ml). The precipitate so washed was then dried under a reduced pressure.There was thus obtained 4.8 g of a yellow-colored powder (thecomposition of this invention) consisting essentially of numerous fineparticles which each were formed substantially from a homogeneousmixture comprising the amorphous substance of Cefditoren pivoxil andhydroxypropylmethyl cellulose.

The total content of hydroxypropylmethyl cellulose and hydroxypropylcellulose contained in the fine particles present in the resultingyellow-colored powder was calculated to be 1.1% (by weight) based on theweight of the Cefditoren pivoxil component.

The fine particles obtained here were placed in and examined by thepowder X-ray diffraction analyzer. The result of analysis of the patternof the resulting X-ray diffraction chart indicated that no peak was seenin the angle of diffraction, and therefore that the Cefditoren pivoxilcomponent contained in the fine particles was present in the form of theamorphous substance. Further, an examination was made under an electronmicroscope in respect of several ones of the fine particles to show thatthe surface of the fine particles had a simple and uniform phase ortexture.

It is deemed that the fine particles present in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and hydroxypropylmethyl cellulose, while the surface layer ofthe fine particles is formed of a homogeneous mixture comprising theamorphous substance of Cefditoren pivoxil, hydroxypropylmethyl celluloseand hydroxypropyl cellulose.

EXAMPLE 8

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved over10 minutes in an acidic aqueous solution (35 ml) containinghydroxypropylmethyl cellulose (100 mg) as dissolved therein and HCl at aconcentration of 1N, at a temperature of 5° C. or lower. Thus, there wasprepared an acidic aqueous solution (pH 0.7) in which Cefditorenpivoxil, hydroxypropylmethyl cellulose and hydrochloric acid werecompletely dissolved.

The acidic aqueous solution obtained here was neutralized to a pH of 7.0by a dropwise slow addition of a 1N aqueous ammonia (about 34 ml), whilethe acidic aqueous solution being maintained at a temperature of 5° C.or lower. The time taken for the completion of the dropwise addition ofthe aqueous ammonia was 30 minutes. During the neutralization reaction,precipitate slowly deposited. The so obtained neutralization reactionsolution containing the precipitate was stirred at a temperature of 5°C. or lower overnight.

The neutralization reaction mixture obtained as above was filtered tocollect the precipitate. The resulting precipitate was washed well withan aqueous solution of 0.5% (by weight) of hydroxypropyl cellulose (15ml). The precipitate so washed was then dried under a reduced pressure.There was thus obtained 5 g of a yellow-colored powder (the compositionof this invention) consisting essentially of numerous fine particleswhich each were formed substantially from a homogeneous mixturecomprising the amorphous substance of Cefditoren pivoxil andhydroxypropylmethyl cellulose.

The total content of hydroxypropylmethyl cellulose plus hydroxypropylcellulose contained in the fine particles present in the resultingyellow-colored powder was calculated to be 2.0% (by weight) based on theweight of the Cefditoren pivoxil component.

The fine particles obtained were placed in and examined by the powderX-ray diffraction analyzer. The result of analysis of the pattern of theresulting X-ray diffraction chart indicated that no peak was appearingin the angle of diffraction, and therefore that the Cefditoren pivoxilcomponent contained in the fine particles was present in the form of theamorphous substance.

It is deemed that the fine particles present in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and hydroxypropylmethyl cellulose, but the surface layer of thefine particles is formed of a homogeneous mixture comprising theamorphous substance of Cefditoren pivoxil, hydroxypropylmethyl celluloseand hydroxypropyl cellulose.

EXAMPLE 9

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved over10 minutes in an acidic aqueous solution (35 ml) containinghydroxypropylmethyl cellulose (40 mg) as dissolved therein and HCl at aconcentration of 1N at a temperature of 5° C. or lower. Thus, there wasprepared an acidic aqueous solution (pH 0.4) in which Cefditorenpivoxil, hydroxypropylmethyl cellulose and hydrochloric acid werecompletely dissolved.

The resulting acidic aqueous solution obtained here was neutralized to apH of 6.9 by a dropwise slow addition of a 1N aqueous ammonia (about 34ml), while the acidic aqueous solution being maintained at a temperatureof 5° C. or lower. The time taken for the completion of the dropwiseaddition of the aqueous ammonia was 30 minutes. During theneutralization reaction, precipitate slowly deposited. The resultingneutralization reaction solution containing the precipitate as formedwas stirred overnight at a temperature of 5° C. or lower.

The neutralization reaction mixture obtained as above was then filteredto collect the precipitate. The resulting precipitate was washed wellwith an aqueous solution of 0.5% (by weight) of hydroxypropyl cellulose(15 ml). The precipitate so washed was then dried under a reducedpressure. There was thus obtained 5 g of a yellow-colored powder (thecomposition of this invention) consisting essentially of numerous fineparticles which each were formed substantially from a homogeneousmixture comprising the amorphous substance of Cefditoren pivoxil andhydroxypropylmethyl cellulose.

The total content of hydroxypropylmethyl cellulose and hydroxypropylcellulose contained in the fine particles present in the resultingyellow-colored powder was calculated to be 1.1% (by weight) based on theweight of the Cefditoren pivoxil component.

The fine particles thus obtained were placed in and examined by thepowder X-ray diffraction analyzer. The result of analysis of the patternof the resulting X-ray diffraction chart indicated that no peak wasappearing in the angle of diffraction, and therefore that the Cefditorenpivoxil component contained in the fine particles was present in theform of the amorphous substance.

It is deemed that the fine particles present in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and hydroxypropylmethyl cellulose, but the surface layer of thefine particles is formed of a homogeneous mixture comprising theamorphous substance of Cefditoren pivoxil, hydroxypropylmethyl celluloseand hydroxypropyl cellulose.

EXAMPLE 10

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved over10 minutes in an acidic aqueous solution (35 ml) containinghydroxypropyl cellulose (50 mg) as dissolved therein and HCl at aconcentration of 1N at a temperature of 5° C. or lower. Thus, there wasprepared an acidic aqueous solution (pH 0.7) in which Cefditorenpivoxil, hydroxypropyl cellulose and hydrochloric acid were completelydissolved.

The resulting acidic aqueous solution obtained here was neutralized to apH of 6.7 by a dropwise slow addition of a 1N aqueous ammonia (about 34ml), while the acidic aqueous solution being maintained at a temperatureof 5° C. or lower. The time taken for the completion of the dropwiseaddition of the aqueous ammonia was 36 minutes. During theneutralization reaction, precipitate slowly deposited. The resultingneutralization reaction solution containing the precipitate as formedwas stirred overnight at a temperature of 5° C. or lower.

The neutralization reaction mixture obtained as above was filtered tocollect the precipitate. The resulting precipitate was washed well withan aqueous solution of 0.5% (by weight) of hydroxypropylmethyl cellulose(15 ml). The precipitate so washed was then dried under a reducedpressure. There was thus obtained 5 g of a yellow-colored powder (thecomposition of this invention) consisting essentially of numerous fineparticles which each were formed substantially from a homogeneousmixture comprising the amorphous substance of Cefditoren pivoxil andhydroxypropyl cellulose.

The total content of hydroxypropyl cellulose and hydroxypropylmethylcellulose contained in the fine particles present in the resultingyellow-colored powder was calculated to be 1% (by weight) based on theweight of the Cefditoren pivoxil component.

The fine particles thus obtained were placed in and examined by thepowder X-ray diffraction analyzer. The result of analysis of the patternof the resulting X-ray diffraction chart indicated that no peak wasappearing in the angle of diffraction in said chart, and therefore thatthe Cefditoren pivoxil component contained in the fine particles waspresent in the form of the amorphous substance.

It is deemed that the fine particles present in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and hydroxypropyl cellulose, but the surface layer of the fineparticles is formed of a homogeneous mixture comprising the amorphoussubstance of Cefditoren pivoxil, hydroxypropyl cellulose andhydroxypropylmethyl cellulose.

EXAMPLE 11

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved over10 minutes in an acidic aqueous solution (35 ml) containinghydroxypropyl cellulose (50 mg) as dissolved therein and HCl at aconcentration of 1N at a temperature of 5° C. or lower. Thus, there wasprepared an acidic aqueous solution (pH 0.3) in which Cefditorenpivoxil, hydroxypropyl cellulose and hydrochloric acid were completelydissolved.

The resulting acidic aqueous solution obtained here was neutralized to apH of 6.9 by a dropwise slow addition of a 1N aqueous ammonia (about34.5 ml), while the acidic aqueous solution being maintained at atemperature of 5° C. or lower. The time taken for the completion of thedropwise addition of the aqueous ammonia was 43 minutes. During theneutralization reaction, precipitate slowly deposited. The resultingneutralization reaction solution containing the precipitate as formedwas stirred at a temperature of 5° C. or lower overnight.

The neutralization reaction mixture obtained as above was filtered tocollect the precipitate. The resulting precipitate was washed well withan aqueous solution of 0.5% (by weight) of methyl cellulose (15 ml). Theprecipitate so washed was then dried under a reduced pressure. There wasthus obtained 4.9 g of a yellow-colored powder (the composition of thisinvention) consisting essentially of numerous fine particles which eachwere formed substantially from a homogeneous mixture comprising theamorphous substance of Cefditoren pivoxil and hydroxypropyl cellulose.

The total content of hydroxypropyl cellulose and methyl cellulosecontained in the fine particles present in the resulting yellow-coloredpowder was calculated to be 1% (by weight) based on the weight of theCefditoren pivoxil component.

The fine particles thus obtained were placed in and examined by thepowder X-ray diffraction analyzer. The result of analysis of the patternof the resulting X-ray diffraction chart indicated that no peak wasappearing in the angle of diffraction in said chart, and therefore thatthe Cefditoren pivoxil component contained in the fine particles waspresent in the form of the amorphous substance.

It is deemed that the fine particles contained in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and hydroxypropyl cellulose, but the surface layer of the fineparticles is formed of a homogeneous mixture comprising the amorphoussubstance of Cefditoren pivoxil, hydroxypropyl cellulose and methylcellulose.

EXAMPLE 12

The crystalline substance (5 g) was dissolved over 10 minutes in anacidic aqueous solution (35 ml) containing hydroxypropylmethyl cellulose(50 mg) as dissolved therein and 1N-HCl at a temperature of 5° C. orlower. Thus, there was prepared an acidic aqueous solution (pH 1.1) inwhich Cefditoren pivoxil, hydroxypropylmethyl cellulose and hydrochloricacid were completely dissolved.

The resulting acidic aqueous solution obtained here was neutralized to apH of 7.0 by a dropwise slow addition of a 1N aqueous ammonia (about 34ml), while the acidic aqueous solution being maintained at a temperatureof 5° C. or lower. The time taken for the completion of the dropwiseaddition of the aqueous ammonia was 50 minutes. During theneutralization reaction, precipitate slowly deposited. The resultingneutralization reaction solution containing the precipitate as formedwas stirred at a temperature of 5° C. or lower overnight.

The neutralization reaction mixture here obtained as above was filteredto collect the precipitate. The resulting precipitate was washed wellwith an aqueous solution of 0.5% (by weight) of hydroxypropyl cellulose(15 ml). The precipitate so washed was then dried under a reducedpressure. There was thus obtained 4.9 g of a yellow-colored powder (thecomposition of this invention) consisting essentially of numerous fineparticles which each were formed substantially from a homogeneousmixture comprising the amorphous substance of Cefditoren pivoxil andhydroxypropylmethyl cellulose.

The total content of hydroxypropylmethyl cellulose and hydroxypropylcellulose contained in the fine particles present in the resultingyellow-colored powder was calculated to be 1.1% (by weight) based on theweight of the Cefditoren pivoxil component.

The fine particles thus obtained were placed in and examined by thepowder X-ray diffraction analyzer. The result of analysis of the patternof the resulting X-ray diffraction chart indicated that no peak wasappearing in the angle of diffraction in the chart, and therefore thatthe Cefditoren pivoxil component contained in the fine particles waspresent in the form of the amorphous substance.

It is deemed that the fine particles contained in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and hydroxypropylmethyl cellulose, but the surface layer of thefine particles is formed of a homogeneous mixture comprising theamorphous substance of Cefditoren pivoxil, hydroxypropylmethyl celluloseand hydroxypropyl cellulose.

EXAMPLE 13

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved over16 minutes in an acidic aqueous solution (35 ml) containing methylcellulose (50 mg) as dissolved therein and HCl at a concentration of 1N,at a temperature of 5° C. or lower. Thus, there were prepared an acidicaqueous solution (pH 0.4) in which Cefditoren pivoxil, methyl celluloseand hydrochloric acid were completely dissolved.

The resulting acidic aqueous solution obtained here was neutralized to apH of 6.7 by a dropwise slow addition of a 1N aqueous ammonia (about 34ml), while the acidic aqueous solution being maintained at a temperatureof 5° C. or lower. The time taken for the completion of the dropwiseaddition of the aqueous ammonia was 40 minutes. During theneutralization reaction, precipitate slowly deposited. The resultingneutralization reaction solution containing the precipitate as formedwas stirred at a temperature of 5° C. or lower overnight.

The neutralization reaction mixture here obtained as above was filteredto collect the precipitate. The resulting precipitate was washed wellwith an aqueous solution of 0.5% (by weight) of hydroxypropyl cellulose(15 ml). The precipitate so washed was then dried under a reducedpressure. There was thus obtained 4.9 g of a yellow-colored powder (thecomposition of this invention) consisting essentially of numerous fineparticles which each were formed substantially from a homogeneousmixture comprising the amorphous substance of Cefditoren pivoxil andmethyl cellulose.

The total content of methyl cellulose and hydroxypropyl cellulosecontained in the fine particles present in the resulting yellow-coloredpowder was calculated to be 2% (by weight) based on the weight of theCefditoren pivoxil component.

The fine particles thus obtained were placed in and examined by thepowder X-ray diffraction analyzer. The result of analysis of the patternof the resulting X-ray diffraction chart indicated that no peak wasappearing in the angle of diffraction in the chart, and therefore thatthe Cefditoren pivoxil component contained in the fine particles waspresent in the form of the amorphous substance.

It is deemed that the fine particles present in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and methyl cellulose, but the surface layer of the fineparticles is formed of a homogeneous mixture comprising the amorphoussubstance of Cefditoren pivoxil, methyl cellulose and hydroxypropylcellulose.

EXAMPLE 14

The crystalline substance of Cefditoren pivoxil (5 g) was dissolved over10 minutes in an acidic aqueous solution (35 ml) containing methylcellulose (50 mg) as dissolved therein and HCl at a concentration of 1Nat a temperature of 5° C. or lower. Thus, there was prepared an acidicaqueous solution (pH 0.3) in which Cefditoren pivoxil, methyl celluloseand hydrochloric acid were completely dissolved.

The resulting acidic aqueous solution obtained here was then neutralizedto a pH of 6.7 by a dropwise slow addition of a 1N aqueous ammonia(about 34.5 ml), while the acidic aqueous solution being maintained at atemperature of 5° C. or lower. The time taken for the completion of thedropwise addition of the aqueous ammonia was 23 minutes. During theneutralization reaction, precipitate slowly deposited. The resultingneutralization reaction solution containing the precipitate as producedwas stirred at a temperature of 5° C. or lower overnight.

The neutralization reaction mixture obtained as above was filtered tocollect the precipitate. The resulting precipitate was washed well withan aqueous solution of 0.5% (by weight) of hydroxypropylmethyl cellulose(15 ml). The precipitate so washed was then dried under a reducedpressure. There was thus obtained 4.9 g of a yellow-colored powder (thecomposition of this invention) consisting essentially of numerous fineparticles which each were formed substantially from a homogeneousmixture comprising the amorphous substance of Cefditoren pivoxil andmethyl cellulose.

The total content of methyl cellulose and hydroxypropylmethyl cellulosecontained in the fine particles present in the resulting yellow-coloredpowder was calculated to be 1.1% (by weight) based on the weight of theCefditoren pivoxil component.

The fine particles thus obtained were placed in and examined by thepowder X-ray diffraction analyzer. The result of analysis of the patternof the resulting X-ray diffraction chart indicated that no peak wasappearing in the angle of diffraction in the chart, and therefore thatthe Cefditoren pivoxil component contained in the fine particles waspresent in the form of the amorphous substance.

It is deemed that the fine particles contained in the yellow-coloredpowder as obtained in this Example have such structure that the centralportion or core portion of these fine particles is formed of ahomogeneous mixture comprising the amorphous substance of Cefditorenpivoxil and methyl cellulose, but the surface layer of the fineparticles is formed of a homogeneous mixture comprising the amorphoussubstance of Cefditoren pivoxil, methyl cellulose andhydroxypropylmethyl cellulose.

Test Example 1

There was taken as a sample one gram of the yellow-colored powder (thecomposition of this invention), which was obtained in Example 6 above,and which consisted essentially of the particles as formed substantiallyfrom a homogeneous mixture comprising the amorphous substance ofCefditoren pivoxil and hydroxypropylmethyl cellulose, and in which thesurface layer of said particles contained additionally hydroxypropylcellulose. The sample so taken was placed in 250 ml of an acidic water(pH 1.2) containing about 1N HCl at 37° C. and stirred at 37° C. for 2hours. The resulting aqueous solution was passed through a millipore (1μm) membrane filter to remove the insoluble solid therefrom. Thetransparent aqueous solution here obtained, which contained Cefditorenpivoxil and the water-soluble cellulose derivatives above-mentioned asdissolved therein, was then measured in respect of the concentration ofthe Cefditoren pivoxil. By this measuring test, the amorphous substanceof Cefditoren pivoxil contained in said yellow-colored powder was foundto have a solubility of at least 4 mg/ml in said acidic water at 37° C.

On the other hand, a test similar to that given in the above was carriedout to measure the solubility of the crystalline substance of Cefditorenpivoxil (the orthorhomic crystalline substance of Cefditoren pivoxil asobtained in Example 1 of the PCT application International Open-LayingPublication No. WO98/12200), which was used as the starting material.This crystalline substance of Cefditoren pivoxil was found to have asolubility of only about 0.4 mg/ml in the above-mentioned acidic waterat 37° C.

Test Example 2

Five grams of the yellow-colored powdery composition as obtained in theabove Example 6 were placed in a sealed container and then storedtherein at 40° C. under an atmosphere of dry air for 4 months. After thestorage, the yellow-colbred powdery composition was taken out from thecontainer, and measured for its X-ray diffraction in the powder X-raydiffraction analyzer same as that used in Example 6. An analysis of thepattern of the resulting X-ray diffraction chart indicated that no peakwas appearing in the angle of diffraction in the chart. It was thusfound that the Cefditoren pivoxil contained in the fine particlespresent in the above-mentioned yellow-colored powder, even after itsstorage at 40° C. for 4 months, could remain in the form of theamorphous substance and therefore has a crystallographical stability.

Industrial Applicability

The yellow-colored powdery composition consisting essentially of theparticles as formed from a homogeneous mixture of the amorphoussubstance of Cefditoren pivoxil with a water-soluble high-molecularadditive, for example, a water-solubilized cellulose derivative is nowprovided according to this invention, and said composition is orallyadministrable and is useful as such an orally administrableantibacterial agent which has a broad antibacterial spectrum. TheCefditoren pivoxil component contained in this composition has a highsolubility in an HCl-acidified water having a pH value of about 1.2 andhence the composition of this invention can exhibit a high therapeuticefficacy when administered orally.

What is claimed is:
 1. A process for the preparation of a yellow-coloredpowdery composition consisting essentially of particles which each areformed of a homogeneous mixture of a crystallographically stable,amorphous and water-soluble substance of Cefditoren pivoxil with awater-soluble high-molecular weight additive, and which particles have auniform, internal texture within each particle, characterized in thatthe process comprises a step of dissolving an orthorhombic crystallinesubstance of Cefditoren pivoxil in an acidic aqueous solution whichcontains a water-soluble high-molecular weight additive made of either awater-solubilized derivative of cellulose as chosen fromhydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate,hydroxypropyl cellulose and methyl cellulose and a pharmaceuticallyacceptable alkali metal salt or alkaline earth metal salt ofcarboxymethyl cellulose, or pluran, carrageenan, polyvinylpyrrolidone oran alginic acid ester of polypropylene glycol dissolved at aconcentration of 0.05% to 1% (weight/weight basis), and said acidicaqueous solution also contains hydrochloric acid, phosphoric acid,sulfuric acid, acetic acid, propionic acid or butyric acid at aconcentration of 0.1N˜12N of the acid, so that the amount of Cefditorenpivoxil dissolved in said acidic aqueous solution is in the range of 10times to 130 times based on the entire weight of said water-solublehigh-molecular weight additive contained in said acidic aqueoussolution, resulting in an acidic aqueous solution containing Cefditorenpivoxil, the water-soluble high-molecular weight additive and the aciddissolved therein, a step of subsequently neutralizing the acidicaqueous solution by adding slowly thereto an aqueous solution selectedfrom the group consisting of an aqueous solution of sodium or potassiumhydroxide, an aqueous solution of sodium or potassium hydrogencarbonate, an aqueous solution of sodium or potassium carbonate and anaqueous solution of ammonium hydroxide, singly or in combination, whilemaintaining said acidic aqueous solution at a temperature of 10° C. orbelow under stirring, and with the amount of said basic sodium orpotassium compound or ammonium hydroxide to be added to said acidicaqueous solution being so adjusted that the resulting reaction solutionafter the neutralization has a pH value of 6.5˜7.1, and a step ofcontinuing during the neutralization reaction the stirring of theaqueous solution containing Cefditoren pivoxil at a temperature of 10°C. or below, to bring about co-precipitation of Cefditoren pivoxil andthe water-soluble high-molecular weight additive simultaneously from theaqueous solution, a step of collecting by filtration or centrifugation,the deposited precipitate from the resulting neutralization reactionmixture, a step of washing the collected precipitate with an aqueoussolution of a water-soluble high-molecular weight additive made of thesame substance as that of the first-mentioned water-solublehigh-molecular weight additive and containing said additive dissolved insaid solution at a concentration of 0.5%˜10% (weight/weight basis),while at least a portion of said water-soluble high-molecular weightadditive used in the washing aqueous solution is transferred from thewashing aqueous solution of the water-soluble high-molecular weightadditive onto the surfaces of the particles of said precipitate, and astep of then drying the washed precipitate, to afford the yellow-coloredpowdery composition consisting essentially of the particles each formedof the homogeneous mixture of the crystallographically stable, amorphousand water-soluble substance of Cefditoren pivoxil with theabove-mentioned water-soluble high-molecular weight additive present ina proportion of 0.5%˜5% based on the weight of the Cefditoren pivoxilsubstance.
 2. A process as claimed in claim 1, which process comprises astep of dissolving the orthorhombic substance of Cefditoren pivoxil inan acidic aqueous solution which contains a water-soluble high-molecularweight additive chosen from hydroxypropylmethyl cellulose, hydroxypropylcellulose, methyl cellulose and polyvinylpyrrolidone dissolved at aconcentration of 0.05% to 1% (weight/weight basis) and which acidicaqueous solution also contains hydrochloric acid or phosphoric acid at aconcentration of 0.5N˜2.0N of the acid, so that the amount of Cefditorenpivoxil dissolved in said acidic aqueous solution is in a range of 10times to 100 times based on the entire weight of said water-solublehigh-molecular weight additive contained in said acidic aqueoussolution, and so that there is prepared an acidic aqueous solutioncontaining Cefditoren pivoxil, the water-soluble high-molecular additiveand the acid dissolved therein, a step of subsequently neutralizing thesaid acidic aqueous solution containing Cefditoren pivoxil, by addingslowly thereto a 1N˜2N aqueous sodium hydroxide solution and/or a 1N˜2Naqueous sodium hydrogen carbonate solution, or by adding slowly theretoa 1N˜2N aqueous ammonium hydroxide solution, while maintaining saidacidic aqueous solution at a temperature of 5° C. or below understirring, until said acidic aqueous solution is neutralized to a pHvalue of 6.5˜7.0, a step of continuing during the neutralizationreaction the stirring of the resulting neutralization reaction mixtureat a temperature of 5° C. or below, to bring about co-precipitation ofCefditoren pivoxil and the water-soluble high-molecular weight additivesimultaneously from said aqueous solution, a step of collecting thedeposited precipitate from the resulting neutralization reactionmixture, a step of washing the collected precipitate with an aqueoussolution of a water-soluble high-molecular weight additive made of thesame substance as that of the first-mentioned water-solublehigh-molecular weight additive and containing said additive dissolved insaid solution at a concentration of 0.5%˜10% (weight/weight basis), anda step of then drying the washed precipitate, to afford theyellow-colored powdery composition consisting essentially of theparticles each formed of a homogeneous mixture of the amorphoussubstance of Cefditoren pivoxil with the above-mentioned water-solublehigh-molecular additive present in a proportion of 1%˜3% based on theweight of the Cefditoren pivoxil substance.
 3. A process for thepreparation of a yellow-colored powdery composition consistingessentially of particles which each comprise mixtures of acrystallographically stable, amorphous and water-soluble substance ofCefditoren pivoxil with water-soluble high-molecular weight additive oradditives, wherein said particles have a uniform, internal texturewithin each particle, characterized in that the process comprises a stepof dissolving an orthorhombic substance of Cefditoren pivoxil in anacidic aqueous solution which contains a first water-solublehigh-molecular weight additive made of either a water-solubilizedderivative of cellulose as chosen from hydroxypropylmethyl cellulose,hydroxypropylmethyl cellulose phthalate, hydroxypropyl cellulose andmethyl cellulose and a pharmaceutically acceptable alkali metal salt oralkaline earth metal salt of carboxymethyl cellulose, or pluran,carrageenan, polyvinylpyrrolidone or an alginic acid ester ofpolypropylene glycol dissolved at a concentration of 0.05%˜1%(weight/weight basis) and wherein said acidic aqueous solution alsocontains hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid,propionic acid or butyric acid at a concentration of 0.1N˜12N of theacid, so that the amount of Cefditoren pivoxil dissolved in said acidicaqueous solution is in a range of 10 times to 130 times based on thewhole weight of said first water-soluble high-molecular weight additivecontained in said acidic aqueous solution, resulting in an acidicaqueous solution containing Cefditoren pivoxil, the water-solublehigh-molecular weight additive and the acid dissolved therein, a step ofsubsequently neutralizing the said acidic aqueous solution, by addingslowly thereto an aqueous solution selected from the group consisting ofan aqueous solution of sodium or potassium hydroxide, an aqueoussolution of sodium or potassium hydrogen carbonate and an aqueoussolution of sodium or potassium carbonate, singly or in combination, orby adding slowly thereto an aqueous solution of ammonium hydroxide,while maintaining said acidic aqueous solution at a temperature of 10°C. or below under stirring, and with the amount of the basic sodium orpotassium compound or ammonium hydroxide to be added to said acidicaqueous solution adjusted so that the reaction solution after theneutralization has a pH value of 6.5˜7.1, a step of continuing duringthe neutralization reaction the stirring of the aqueous solutioncontaining Cefditoren pivoxil at a temperature of 10° C. or below, tobring about co-precipitation of Cefditoren pivoxil and the firstwater-soluble high-molecular weight additive simultaneously from theaqueous solution, a step of collecting by filtration or centrifugationthe precipitate from the resulting neutralization reaction mixture, astep of washing the collected precipitate with an aqueous solution whichcontains a second, water-soluble high-molecular weight additive made ofa substance different from the above-mentioned first, water-solublehigh-molecular weight additive contained in said acidic aqueous solutioncontaining Cefditoren pivoxil, and which aqueous solution is containingsaid second high molecular weight additive dissolved therein at aconcentration of 0.5%˜10% (weight/weight basis), while at least aportion of said second water-soluble high-molecular weight additive usedin the washing aqueous solution is transferred from the washing aqueoussolution of the second water-soluble high-molecular weight additive ontothe surfaces of the particles of the precipitate, and a step of thendrying the washed precipitate, to afford the yellow-colored powderycomposition consisting essentially of such particles which each containCefditoren pivoxil, and of which the central portion or core portion ofeach particle is formed only from a homogeneous mixture of thecrystallographically stable, amorphous and water-soluble substance ofCefditoren pivoxil with the first water-soluble high-molecular weightadditive present in a proportion of 0.5%˜5% based on the weight of saidCefditoren pivoxil substance, and of which the surface layer of eachparticle is formed from a homogeneous mixture of thecrystallographically stable, amorphous and water-soluble substance ofCefditoren pivoxil with said first water-soluble high-molecular weightadditive and also with said second water-soluble high-molecular weightadditive.
 4. A process as claimed in claim 3, which process comprises astep of dissolving the orthorhombic substance of Cefditoren pivoxil inan acidic aqueous solution which contains a water-soluble high-molecularweight additive as chosen from hydroxypropylmethyl cellulose,hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidonedissolved at a concentration of 0.05%˜1% (weight/weight basis) and whichacidic aqueous solution also contains hydrochloric acid or phosphoricacid at a concentration of 0.5N˜2.0N of the acid, so that the amount ofCefditoren pivoxil dissolved in the acidic aqueous solution is in arange of 10 times to 100 times based on the entire weight of said firstwater-soluble high-molecular weight additive contained in said acidicaqueous solution, resulting in an acidic aqueous solution containingCefditoren pivoxil, the water-soluble high-molecular weight additive andthe said acid dissolved therein, a step of subsequently neutralizing theacidic aqueous solution containing Cefditoren pivoxil, by adding slowlythereto an aqueous 1N˜2N sodium hydroxide solution and/or an aqueous1N˜2N sodium hydrogen carbonate solution or by adding slowly thereto anaqueous 1N˜2N ammonium hydroxide solution, while maintaining the acidicaqueous solution at a temperature of 5° C. or below under stirring,until the acidic aqueous solution is neutralized to a pH value of6.5˜7.0, a step of continuing the stirring of the neutralizationreaction mixture at a temperature of 5° C. or below during theneutralization reaction, to bring about the co-precipitation ofCefditoren pivoxil and said first water-soluble high-molecular weightadditive simultaneously from the aqueous solution, a step of collectingthe deposited precipitate from the resulting neutralization reactionmixture, a step of washing the collected precipitate with an aqueoussolution which contains, as the second water-soluble high-molecularweight additive made of a substance different from the above-mentionedfirst water-soluble high-molecular weight additive, a water-solublehigh-molecular weight additive chosen from hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose andpolyvinylpyrrolidone, and which aqueous solution contains said secondhigh-molecular weight additive dissolved therein at a concentration of0.5%˜10% (weight/weight basis), while at least a portion of the secondwater-soluble high-molecular weight additive used in the washing aqueoussolution is transferred from said aqueous solution of the secondwater-soluble high-molecular weight additive onto the surfaces of theparticles of the precipitate, and a step of then drying the washedprecipitate, to afford the yellow-colored powdery composition consistingessentially of such particles of which the central portion or coreportion of each particle is formed only from a homogeneous mixture ofthe amorphous substance of Cefditoren pivoxil with said firstwater-soluble high-molecular weight additive, and of which the surfacelayer of each particle is formed from a homogeneous mixture of theamorphous substance of Cefditoren pivoxil with said first water-solublehigh-molecular weight additive and also with said second water-solublehigh-molecular weight additive.